Hepatitis C virus (HCV) is a major causative agent of acute and chronic hepatitis worldwide. HCV infection affects more than 200 million people worldwide and represents a significant health problem in many countries (Lauer and Walker, N Engl J Med 2001; 345: 41-52; Shepard et al., Lancet Infect Dis 2005; 5:558-567.). Approximately 20-40% of individuals infected with HCV clear the virus during the acute phase, whereas the remaining 60-80% develop chronic disease which may result in hepatic failure and liver cancer (Villano et al., Hepatology 1999; 29:908-914; Seeff, Hepatology 2002; 36:S35-S46; Cox et al., Clin Infect Dis 2005; 40:951-958). There is at present no preventative composition, and therapeutic options are currently limited to interferon/ribavirin therapy (see below), which is often poorly tolerated, is contraindicated in many subjects, and is expensive. In addition, the efficacy of the current standard treatment with interferon and ribavirin is limited, especially in genotype 1, the most prevalent genotype in the U.S. and most industrialized countries (Dienstag and McHutchison, Gastroenterology 2006; 130:231-264). Thus, only a proportion of HCV-infected persons can be successfully treated using current standard of care regimens.
HCV is a non-cytopathic virus that induces both acute and chronic hepatitis and interacts in a highly complex manner with the immune system (Rehermann and Nascimbeni, Nat Rev Immunol 2005; 5:215-229). Likewise, the immune system has a unique role in the pathogenesis of HCV infection, as it contributes both to control of viral infection and liver repair, but also to the development of chronic infection and liver cirrhosis.
As mentioned above, the current Standard Of Care (SOC) for the treatment of chronic hepatitis C is pegylated interferon-alpha plus ribavirin combination therapy, where the interferon is typically administered by subcutaneous injection once weekly for 24 weeks (HCV genotypes 2 and 3) or 48 weeks (HCV genotypes 1 and 4), with daily doses of ribavirin. While interferon/ribavirin therapy is relatively efficacious in patients suffering from genotype 2 or 3 HCV infection (˜85% of patients reach Sustained Virologic Response (SVR)), about 50% of patients infected with genotype 1 HCV do not reach SVR. Moreover, the current SOC is poorly tolerated—interferons are proinflammatory cytokines that are known to cause side effects, including flu-like symptoms and depression, and ribavirin induces hemolytic anemia in 20-30% of patients. When used together as Standard of Care (SOC), adverse events reported include flu-like symptoms (e.g., fever, headache, chills), gastrointestinal issues (e.g., nausea, anorexia, diarrhea), neuropsychiatric disorders (e.g., depression), skin disorders, and hematological disorders. These side effects often lead to patient non-compliance or discontinuation of treatment, and require erythropoietin rescue and/or dose reductions in 10-20% of patients.
The behavior of the serum HCV RNA levels in chronic HCV has been predicted in various settings using a 3 compartment model of viral kinetics, which includes uninfected liver cells, infected liver cells, and free virus in the serum. Viral levels in the peripheral blood early during the course of interferon (IFN) therapy have served as an early predictor of response to therapy due to the fact that they can be measured easily and have been correlated to other more meaningful endpoints in the setting of long-term IFN treatment, such as Sustained Virologic Response (SVR, defined as negative peripheral viral levels for at least 6 months after the completion of IFN-based therapy). Viral clearance in the setting of interferon therapy is bi-phasic; a rapid early phase of peripheral viral load reduction which occurs in the first week(s) (phase 1), followed by the rate limiting, gradual second phase of peripheral viral load reduction which occurs over many months (phase 2) (Layden-Almer et al., J Viral Hep 2006; 13:499-504; Herrmann and Zeuzem S. Eur J Gastroenterol Hepatol 2006; 18:339-342). While phase 1 kinetics reflect the efficiency of inhibition of viral replication (driven by rapid peripheral viral clearance), phase 2 kinetics represent direct clearance of infected liver cells. Clearance of infected hepatocytes is the rate limiting step in achieving complete eradication of hepatic infection and SVR.
While the ultimate goal of therapy is SVR, there are several early prognostic endpoints that serve as markers to guide patient treatment. These endpoints are summarized in Table 1 below.
TABLE 1EndpointDefinitionPredictive ValueRapid VirologicViral negativity at90-100% of RVRs (priorResponse (RVR)week 4 of IFN therapytreatment naïvesubjects) willreach SVR1,2,3Early Virologic>2 log10 reduction<3% of non-EVRs will reachResponse (EVR)in viral load atSVR4; 60-75% of EVRs reachweek 12 ofSVR3,5,6,7interferon therapyComplete EVRViral negativity at~90% of cEVRs will reach(cEVR)week 12 of IFNSVR5therapyEnd of TreatmentViral negativity~80% of ETRs will achieveResponse (ETR)at 48 weeksSVR8(genotype 1)SustainedViral negativity at~98% of subjects achievingVirologic6 months post-ETRSVR24 will remain virusResponse (SVRfree 5 years out9or SVR24)1Yu et al, RVR and treatment duration in CHC: a randomized trial; Hepatology 20082Jensen et al, Early ID of HCV G1 patients responding to 24 wks of treatment; Hepatology 20063Schiffman M L (2007) “New Management Strategies for HCV Nonresponders and Relapsers”4Pegasys prescribing information 2008; Roche5Brandao et al, 24 vs 48 weeks of Pegasys (Riba) in (Geno 1, naives) CHC; J. Viral Hepatitis 2006.6Manns et al, PegIntron (Riba) vs IFN (Riba) in (CHC); Lancet 20017Poordad et al, RVR in the management of CHC: Clin Inf Dis 20088Hoofnagel et al, PegInteferon & Riba case study; NEJM 20089Schering Plough Treatment Outcomes Study
Of the endpoints in Table 1, EVR represents the most important negative predictor of outcome. Patients failing to achieve an EVR (>2 log 10 reduction in viral load) by week 12 on interferon therapy have <3% chance of ultimately achieving an SVR. These patients are routinely taken off therapy to spare them from the significant side effects associated with SOC, since it is believed that the native immune response in these patients is incapable of clearing virally infected cells in the context of 48 weeks of viral suppression. RVR and cEVR are positive predictive endpoints, with approximately 90% of patients ultimately achieving SVR after 48 weeks of pegylated-interferon-based therapy.
Patients are categorized by their response at these virologic endpoints. “Null Responders” are patients that cannot achieve at least a 1 log 10 reduction in viral load by week 12 on SOC; it is believed that these patients may have an impaired immune system. “Non-Responders” are patients who receive a 12-week course of therapy and fail to achieve EVR. “Partial Responders” are defined as patients who have >2 log 10 viral load reduction by 12 weeks, but never achieve viral negativity. These patients have a 20-30% chance of responding to a more aggressive regimen. “Relapsers” are patients who achieve viral eradication (negativity) at end of treatment, but whose viral load returns to detectable levels during the 24 week follow up.
The average patient response to 48 weeks of standard of care in genotype 1 patients has been well characterized. For example, of patients with chronic hepatitis C infection (genotype 1) receiving the SOC therapy of pegylated interferon-α2 (PEGASYS® (Peginterferon alfa-2a; Roche Pharmaceuticals)) plus ribavirin, Table 2 shows the typical expected response for these patients.
TABLE 2ResponseInterferon/Ribavirin Treatment Phenotype of PatientEndpointNaïveRelapserNon-ResponderRVR10-15%1EVR  ~80%157%2  33%2cEVR  ~43%3ETR68-69%4,5,6SVR2446-52%4,6,7,810-15%91Schiffman M L (2007) “New Management Strategies for HCV Nonresponders and Relapsers”2Sporea et al, Randomized Study of Pegasys (Riba) vs PegIntron (Riba); J Gastro Liver Disease, June 20063PROVE 2 study; taken from DM Stakeholder Opinions (Datamonitor Stakeholder Opinions: Hepatitis C “Small molecule antivirals pave the way for triple therapy” December 2007) - 12 wks of triple therapy4Schiffman et al, Pegasys (Riba) v PegIntron (Riba) v Pegasys in CHC; NEJM 20025Poordad et al, RVR in the management of CHC: Clin Inf Dis 20086Jensen et al, Early ID of HCV G1 patients responding to 24 wks of treatment; Hepatology 20067Pegasys prescribing information 2008; Roche8Brandao et al, 24 vs 48 weeks of Pegasys (Riba) in (Geno 1, naives) CHC; J. Viral Hepatitis 2006.9Nevens et al. J Hepatol 2005: 42: A588
Numerous reports suggest that viral replication, the level of viremia, and progression to the chronic state in hepatitis C-infected individuals are influenced directly and indirectly by HCV-specific cellular immunity mediated by CD4+ helper (Th) and CD8+θcytotoxic T lymphocytes (CTLs) (Cooper et al., Immunity 1999; 10:439-449; Gerlac et al., Gastroenterology 1999; 117:933-941; Lechner et al., J Exp Med 2000; 191:1499-1512; Thimme et al., J Exp Med 2001; 194:1395-1406; Shoukry et al., Annual Rev Microbiol 2004; 58:391-424). Studies of humans and chimpanzees have revealed that HCV can replicate for weeks before the onset of CD4+ and CD8+ T cell responses can be detected in the liver and in the blood. Moreover, there may be a delay in the acquisition of function by CD8+ (and perhaps CD4+) T cells even after their expansion in blood (Shoukry, ibid.). The appearance of functional CD8+ T cells is kinetically associated with control of viremia and, at least in some cases, with an elevation in serum transaminases, suggesting that liver damage during acute hepatitis C is immunopathological. At highest risk of persistent HCV infection are those individuals who fail to generate a detectable virus-specific T lymphocyte response in the blood, liver, or both. Perhaps most importantly, generation of a cellular immune response does not necessarily ensure that the infection will be permanently controlled. CD4+ and CD8+ T cell responses must be sustained for weeks or months beyond the point of apparent control of virus replication to prevent relapse and establishment of a persistent infection.
While SOC provides the best current treatment for patients chronically infected with HCV, the significant adverse effects of this regimen that can lead to noncompliance, dose reduction, and treatment discontinuation, combined with the percentage of patients who still fail to respond or sustain response to therapy, leaves opportunities for novel therapeutic treatments for HCV.